Thrombolytic Therapy
Thrombolytic therapy is used to dissolve blood clots (i.e., thrombi). Thrombolytic agents include protein catalysts that activate a plasma proenzyme known as plasminogen to, in turn, produce the active enzyme plasmin. Plasmin then solubilizes fibrin and degrades a number of other plasma proteins, most notably fibrinogen and the procoagulant factors V and Vil. Available thrombolytic agents include urokinase, tissue plasminogen activator (tPA), duteplase (a type of tPA), alteplase (a.k.a. activase, a type of tPA), streptokinase, anistreplase (also known as anisoylated plasminogen-streptokinase activator complex, or APSAC), and tenecteplase (a.k.a. TNKase, a type of tPA).
Indications for thrombolytic therapy include acute myocardial infarction, acute ischemic stroke, acute pulmonary embolism, acute deep venous thrombosis, and a clotted arteriovenous (AV) fistula or shunt. Bleeding is the major complication of thrombolytic therapy. Consequently, absolute contraindications include dissecting aortic aneurysm, pericarditis, hemorrhagic stroke, or neurosurgical procedures within six months or known intracranial neoplasm. Relative contraindications include major surgery or bleeding within six weeks, known bleeding diathesis, and severe uncontrolled hypertension. Streptokinase and anistreplase are potentially allergenic, so patients are usually prophylactically pre-treated with intravenous hydrocortisone.
Studies show that thrombolytic therapy administered within 24 hours of an acute myocardial infarction leads to decreased mortality and morbidity. Of the 900,000 people who have heart attacks in the United States every year, only one-fifth receive thrombolytic drugs of any kind and only one-tenth receive tPA. Streptokinase, an effective clot buster sold at one tenth the price of tPA, is a popular rival of tPA.
A 1995 study showed that, for every 100 carefully selected patients with ischemic stroke and no CT evidence of intracranial hemorrhage treated with tPA within three hours after stroke onset, an additional 12 recover without residual disability. Some evidence suggests that the earlier this therapy is delivered, the more likely the patient is to recover neurological function.
Anticoagulation Therapy
Chronic anticoagulation therapy is used to prevent blood clots, e.g., in patients with a history of thromboembolism formation. The disorders treated with chronic anticoagulation therapy include acute venous thrombosis (e.g., deep venous thrombosis or DVT) or pulmonary embolism. (DVT usually refers to a blood clot in a deep vein of a limb, most commonly one of the legs.) Chronic anticoagulation therapy may also be used to prevent arterial thromboembolism associated with atrial fibrillation, left ventricular thrombus, and other disorders that have demonstrated a significant risk of thromboembolism (e.g., presence of lupus anticoagulant antibody and/or anti-cardiolipin antibody, and paradoxical embolism).
Chronic anticoagulation therapy is also used for prophylaxis of thromboembolism in asymptomatic patients with no history of thrombosis but with a disorder(s) or other risk factor(s) for forming a thromboembolism. Such disorders include chronic or paroxysmal atrial fibrillation, presence of a mechanical cardiac valve, post-operative venous thrombosis, post-myocardial infarction, cardiomyopathy, documented procoagulant disorder with first degree relative with DVT, and presence of a central venous catheter. Chronic anticoagulation therapy may also be used for prophylaxis of thromboembolism during chemotherapy in women with breast cancer.
Cardiovascular Disease
According to 1997 estimates, 60 million Americans have one or more forms of cardiovascular disease. Coronary heart disease affects approximately 12.2 million Americans, with 6.3 million afflicted with angina pectoris. An estimated 7.7 million Americans have suffered a myocardial infarction, and an additional 4.4 million have suffered a stroke. Many of these patients are on chronic anticoagulation therapy. A few were fortunate enough to receive thrombolytic therapy within a few hours following a myocardial infarction or a stroke.
Atrial Fibrillation
Atrial fibrillation (AF), the most commonly encountered arrhythmia in clinical practice, causes significant morbidity and mortality in affected individuals and is a considerable burden on healthcare services. Clinical manifestations range from palpitations through heart failure to cerebral embolism and ischemic stroke. AF is present in 17 to 25% of acute stroke patients and is estimated to increase stroke risk five-fold compared with patients in sinus rhythm.
Studies show that aspirin therapy has a modest benefit, reducing stroke rate by one-fifth, whereas warfarin limits annual incidence of stroke to 1.4%. Such anticoagulant therapy, however, can cause major hemorrhage at a rate of 2.3% per year.
The true prevalence of AF is difficult to establish, but is probably between 0.4 and 1.7% of the adult population, with approximately 20 to 30% of cases displaying a paroxysmal pattern. Community-based studies have demonstrated a male predominance and a striking relationship with increasing age—the prevalence rising from less than 1% at younger than 65 years, 2.3% at 65 to 69 years, 4.1% at 70 to 74 years, 5.8% at 75 to 79 years, 6.4% at 80 to 84 years, and 8.1% at older than 85 years of age. It has been estimated that there are 2.2 million cases of AF in the United States, with a median age of 75 years. Thus, AF is a common condition in the elderly and will only increase as the mean population age rises.
Deep Vein Thrombosis (DVT) and Pulmonary Embolism
Deep venous thrombosis (DVT) is a relatively common disease that is often encountered by family physicians. Epidemiologic data suggest that the annual incidence of a first episode of DVT ranges from 60 to 180 cases per 100,000 people, or more than 300,000 new cases annually in the United States. The cost burden of this disease is quite high, since most patients with DVT require one or more diagnostic tests, treatment with intravenous heparin, and a three- to seven-day hospital stay.
DVT is development of a thrombus of fibrin, red blood cells, platelets, and granulocytes within a deep vein. Thrombi form where blood flow is stagnant and where eddies form along the cusps of valves. The danger lies in pulmonary embolization through thrombus detachment. The embolus floats through veins of increasing diameter to the right side of the heart, where it is pumped to the pulmonary arterial system in the lungs; the embolus lodges where its diameter is greater than the lumen of the artery.
An estimated 500,000 people in the United States will suffer from some degree of pulmonary emboli (PE) this year, and 50,000 will die as a result. Not all PEs are life-threatening; in fact, many people unknowingly have had one or more PEs. The outcome of any PE depends largely on the length, diameter, and number of emboli carried to the lungs. Large emboli are usually 1.0 to 1.5 cm in diameter and can commonly be 5 cm long. The origin of most major PE is the ilio-femoral veins, with relatively fewer coming from the calf veins and the inferior vena cava.
Paradoxical Embolism
Paradoxical embolism is the passage of a clot (thrombus) from a vein to an artery. As described above, when clots in veins break off (embolize), they travel to the right side of the heart and then, normally, to the lungs, where they lodge. The lungs prevent clots from entering the arterial circulation. However, when there is a hole in the wall between the two upper chambers of the heart (an atrial septal defect), a clot can cross from the right to the left side of the heart, then into the arteries as a paradoxical embolism. Once in the arterial circulation, a clot can travel to the brain, block a vessel there, and cause a stroke (cerebrovascular accident). Because of this risk of stroke from paradoxical embolism, even small atrial septal defects are usually repaired.
Warfarin (Coumadin®)
Warfarin is the most frequently prescribed oral anticoagulant, the fourth most prescribed cardiovascular agent, and the overall eleventh most prescribed drug in the United States, with annual sales of approximately $500 million. Nonetheless, in 1995, the Agency for Healthcare Policy and Research (AHCPR) reported that warfarin is greatly underutilized for stroke prevention.
Warfarin is an antagonist of vitamin K, a necessary element in the synthesis of clotting factors II, VII, IX and X, as well as the naturally occurring endogenous anticoagulant proteins C and S. These factors and proteins are biologically inactive without the carboxylation of certain glutamic acid residues. This carboxylation process requires oxidized vitamin K as a cofactor and occurs primarily in the liver. Antagonism of vitamin K or a deficiency of this vitamin reduces the rate at which these factors and proteins are produced, thereby creating a state of anticoagulation.
Therapeutic doses of warfarin reduce the production of functional vitamin K-dependent clotting factors by approximately 30 to 50 percent. A concomitant reduction in the carboxylation of secreted clotting factors yields a 10 to 40 percent decrease in the biologic activity of the clotting factors. As a result, the coagulation system becomes functionally deficient.
Warfarin prolongs the prothrombin time (PT), which is responsive to depression of three of the four vitamin K-dependent coagulation factors (factors II, VIl, and X). The International Normalized Ratio (INR) has been developed and adopted as a method to standardize monitoring of oral anticoagulant therapy. The INR is less reliable as a measure of anticoagulation in the early course of warfarin therapy; however, it is more reliable than the PT or PT ratio for clinical management.
Warfarin does not affect established thrombus and does not reverse ischemic tissue damage. Warfarin therapy prevents further extension of the clot and prevents secondary thromboembolic complications.
Heparin
Heparin is a parenteral anticoagulant widely used in clinical medicine. Compared with low molecular weight heparins, unfractionated heparin produces a less predictable anticoagulant response due primarily to its reduced bioavailability after subcutaneous administration of low doses, its dose-dependent clearance, and differences among patients in the nonspecific binding of heparin to proteins and cells.
Heparin exerts its anticoagulant action by accelerating the activity of antithrombin III (ATIII). The interaction of heparin with ATIII produces a conformational change in ATIII, which accelerates the ability of ATIII to inactivate the coagulation enzymes thrombin (factor IIa), factor Xa, and factor IXa.
The activated partial thromboplastin time (APTT) is usually used to monitor heparin therapy since it is sensitive to the inhibitory effects of heparin on thrombin, factor Xa, and factor IXa. High doses of heparin interfere with platelet aggregation, which, in turn, prolongs bleeding time, although typical doses of heparin do not affect bleeding time.
Heparin does not lyse existing clots. It is important to achieve therapeutic heparin concentrations quickly following a pathological thrombus in order to prevent clot extension.
Prothrombin Time (PT) and International Normalized Ratio (INR) Measurement
The prothrombin time (PT) test essentially monitors the time it takes for a sample of blood to clot after the blood is exposed to a coagulation-promoting agent (thromboplastin). The result of a test is expressed as an International Normalized Ratio (INR), which was developed to reduce variability in PT test results. In order to make PT times comparable across labs, the World Health Organization (WHO) has designated an international reference preparation (IRP) of thromboplastin (rTF/95) as a standard. This allows commercial thromboplastins to be compared to a WHO reference standard and be corrected to adjust to the WHO reference by the International Sensitivity Index (ISI). The INR is then calculated according to the following formula: INR=(Patient PT in seconds/Mean Normal PT in seconds)^ISI.
An INR of 1 typically corresponds to normal blood coagulation. Assuming an ISI of 1, an INR of 2 means that the coagulation time is about twice as long as normal, an INR of 3 equates to about three times as long as normal, and so on.
Alternative Coagulation Assays to PT
In 1994, Le, et al. investigated other coagulation assays in 79 patients attending an anticoagulation clinic. [Le, et al. “The International Normalized Ratio (INR) for Monitoring Warfarin Therapy: Reliability and Relation to Other Monitoring Methods” Annals of Internal Medicine, 1 Apr. 1994; 120: 552-558.] Because determinations of residual specific prothrombin activity and native prothrombin antigen have been proposed as being better techniques for monitoring oral anticoagulant therapy than the prothrombin time, the authors examined the relation between these measurements and INR values. Specifically, they evaluated the Specific Prothrombin Assay and a Native Prothrombin Antigen Assay.
Specific Prothrombin Assay (Factor II): Prothrombin activity was assayed by a one-stage assay in which a mixture of 100 μL of a prothrombin-depleted human serum/barium-adsorbed bovine plasma reagent and 100 μL of a 1:10 to 1:40 dilution of test plasma were clotted by the addition of 200 μL of a thromboplastin C reagent containing CaCl2. Clotting times were converted to percent normal plasma prothrombin activity from a log-log standard curve prepared with dilutions of control pooled plasma.
Native Prothrombin Antigen Assay: The authors measured plasma native prothrombin antigen concentration with native prothrombin antigen enzyme immunoassay kits. Color was measured at 450 nm with a Thermomax enzyme-linked immunosorbent assay reader.
Relations among Values for International Normalized Ratios, Native Prothrombin Antigen, and Specific Prothrombin Activity: The authors confirmed an earlier report of good correlation between residual plasma native prothrombin antigen levels measured by enzyme immunoassay and residual specific prothrombin activity measured by a one-stage coagulation method (r=0.92, n=89). A mean INR range of 2.0 to 3.0 corresponded to between about 40% to 20% residual native plasma prothrombin.
Activated Partial Thromboplastin Time (PTT) Measurement
The intrinsic capability of blood to form a fibrin clot requires coagulation factors XII (Hageman), XI (plasma thromboplastin antecedent), IX (Christmas), VII (anti-hemophilic), X (Stuart-Prower), V (proaccelerin), II (prothrombin), I (fibrinogen), platelet lipid, and calcium. Historically, intrinsic coagulation was measured by timing fibrin clot formation upon recalcification of citrated, anticoagulated, platelet rich plasma. Measurement with platelet rich plasma, however, relied on the platelets as a source of phospholipid to the extent that variables such as centrifugation and patient platelet count had a significant bearing on the test results. The partial thromboplastin time (PTT) introduces a platelet substitute that eliminates test variability due to the availability of platelet phospholipid. By adding a substance to activate factors XII and Xl, the contact factors, the partial thromboplastin time becomes the “activated” partial thromboplastin time (APTT). Because coagulation endpoints are shorter and sharper than with the PTT, the APTT has proven to be a simple and highly reliable measurement of the intrinsic coagulation mechanism.
Laboratory monitoring of heparin therapy is desirable to ensure that an appropriate antithrombotic effect is obtained, while guarding against bleeding complications of an overdosage. Currently, the APTT is the most common test used to monitor heparin therapy. Monitoring by APTT evaluates heparin's overall activity throughout the entire coagulation system i.e., inactivation of thrombin, Xa, Xlla, Xla, and IXa. Heparin treatment is usually monitored to maintain the ratio of the patient's APTT to the mean control APTT within a defined range of approximately 1.5 to 2.5, referred to as the therapeutic range. Laboratory and clinical studies have established a therapeutic range that is equivalent to a heparin level of 0.2 to 0.4 Upper milliliter (mL) by protamine titration, or 0.35 to 0.7 Upper mL according to the level of anti-Xa activity. It should be noted that the responsiveness of the reagents used in APTT tests can vary widely. The therapeutic range for any given APTT reagent should therefore be established in the clinical laboratory to correspond to a heparin level of 0.2 to 0.4 U/mL by protamine titration.
Alternative Coagulation Assays to PTT
Anti-Xa Assay: An alternative approach is to assay for heparin exploiting its catalysis by antithrombin 111 inhibition of coagulation enzymes, particularly factor Xa. The factor Xa inhibition test (anti-Xa assay) is the most useful test for assaying the widest variety of therapeutic heparin preparations. In this method, both factor Xa and antithrombin 111 are present in excess and the residual factor Xa activity is inversely proportional to the heparin concentration. The assumption is made that the patient has a normal concentration of antithrombin III. (For a patient with ATIII deficiency a heparin concentration is measured, but this does not necessarily correspond to the anticoagulant capacity in vivo.) It is recommended to also measure the antithrombin 111 level for all patients under heparin therapy when using this type of assay to ensure normal ATIII activity. The therapeutic range of the anti-Xa assay in the treatment of thromboembolic disease established by laboratory and clinical studies for unfractionated heparin is 0.35 to 0.7 anti-Xa Units/mL. The therapeutic range for LMW heparins has not been well established at this time.
There are several clinical situations where the specific measurement of heparin levels using the anti-factor Xa method may be necessary. Patients receiving heparin but demonstrating an inadequate APTT response can be evaluated for heparin by the anti-Xa assay. Monitoring of heparin is difficult by conventional methods when the baseline APTT is prolonged as seen in patients with lupus anticoagulants and deficiencies of factor XII (Hagemen factor), prekallikrein (Fletcher factor), and high molecular weight kininogen (Fitzgerald factor). A quantitative anti-Xa assay makes heparin monitoring possible in these clinical situations.
Sensing Cardiac Function
A number of means are available for assessing cardiac function. An ultrasound echocardiogram can non-invasively assess a number of parameters of the heart, such as left ventricle size and cardiac output. An electrocardiogram (ECG) may be recorded non-invasively or invasively, and may be used to detect or diagnose a number of cardiac conditions, e.g., ischemia, arrhythmia, etc. Invasive pressure transducers may be used to determine left ventricular end diastolic pressure, pulmonary capillary wedge pressure, and systemic blood pressure. For instance, a thermal dilution catheter, the dye-dilution method, and/or catheter pressure transducers/catheter tip transducers may be used to measure blood pressure or cardiac output. Cardiac output, the total volume of blood pumped by the ventricle per minute, is the product of heart rate and stoke volume.
In a 1990 study of 21 heart transplant patients, Pepke-Zaba, et al. compared cardiac output measured by thermodilution and by impedance cardiography. They found close agreement between the measurements, both at rest and during exercise. Both measurements followed changes in heart rate and oxygen consumption. Both thermodilution and impedance cardiography methods elicited good reproducibility of cardiac output measurements at rest and during exercise. The authors concluded that the noninvasive and continuous record of cardiac output obtained by impedance cardiography can be used for the monitoring of cardiac output. [Pepke-Zaba, et al. “Validation of impedance cardiography measurements of cardiac output during limited exercise in heart transplant recipients” Transplant International, 1990 July;3(2):108-12.]
As should be understood by the foregoing, given the prevalence of thromboembolic disease, alternative treatments and improvements in monitoring, preventing, and treating thromboembolic disease are needed. For instance, a closed-loop system would allow automatic or semi-automatic adjustment of treatment and would allow tighter control of clotting than possible with conventional periodic tests of clotting parameters.